Though respiratory regulation in newborns has many similarities with adults, quantitative and qualitative differences exist. It is possible that these developmental differences account for the pronounced susceptibility of newborn infants to have prolonged spontaneous apnea. The present studies are based on the hypothesis that central neural mechanisms are more important in respiratory regulation than traditionally recognized. The long-range objective is to develop an understanding of central neural mechanisms which destabilize respiratory drive. The specific objective of this study is to characterize the influence of central and peripheral chemosensory mechanisms on the respiratory response to hypoxemia in newborns. An experimental animal model has been developed which eliminates the effect of negative chemical feedback that usually follows a change in ventilation but which allows quantitation of respiratory output by measuring phrenic nerve activity. Two studies are proposed which utilize this model. The first utilizes measurement of brain extracellular fluid pH, PCO2, and C1- to assess change in central chemosensory stimulation to respiration. Our preliminary results indicate that the brainstem regions responsible for chemosensation become alkalotic during hypoxemia in newborn but not older animals. This first study will characterize the maturation of mechanisms by which ECF pH is altered during hypoxia by examining changes in brainstem ECF, PCO2, brainstem blood flow and the effects of various agents which inhibit brainstem buffering capacity. The second study utilizes the above model to determine the role that peripheral chemosensors, particularly the carotid body, have in stimulating respiration during hypoxemia of newborns. In specific, carotid sinus nerve afferent chemosensory activity will be quantified during hypoxemia and the effect of possible inhibitory feedback mechanisms and a new analeptic agent will be assessed. The interaction of central and peripheral chemosensory afferents on the central network of respiratory neurons is critical for maintenance of breathing during hypoxemia. This interaction may have important implications for premature newborns with apnea who are at risk for hypoxic cerebral damage, older infants at risk for the Sudden Infant Death Syndrome, as well as infants and adults with obstructive sleep apnea resulting in hypoxemia.